The Discovery of a Potent, Selective, and Peripherally Restricted Pan-Trk Inhibitor (PF-06273340) for the Treatment of Pain

Skerratt, Sarah E., Andrews, Mark, Bagal, Sharan K., Bilsland, James, Brown, David, Bungay, Peter J., Cole, Susan, Gibson, Karl R, Jones, Russell, Morao, Inaki, and others. (2016) The Discovery of a Potent, Selective, and Peripherally Restricted Pan-Trk Inhibitor (PF-06273340) for the Treatment of Pain. Journal of Medicinal Chemistry, 59 (22). pp. 10084-10099. ISSN 0022-2623. (doi:10.1021/acs.jmedchem.6b00850) (KAR id:59375)

PDF Publisher pdf Language: English This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Download this file (PDF/7MB)
Request a format suitable for use with assistive technology e.g. a screenreader
Official URL: http://doi.org/10.1021/acs.jmedchem.6b00850

Abstract

The neurotrophin family of growth factors, comprised of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4), is implicated in the physiology of chronic pain. Given the clinical efficacy of anti-NGF monoclonal antibody (mAb) therapies, there is significant interest in the development of small molecule modulators of neurotrophin activity. Neurotrophins signal through the tropomyosin related kinase (Trk) family of tyrosine kinase receptors, hence Trk kinase inhibition represents a potentially “druggable” point of intervention. To deliver the safety profile required for chronic, nonlife threatening pain indications, highly kinase-selective Trk inhibitors with minimal brain availability are sought. Herein we describe how the use of SBDD, 2D QSAR models, and matched molecular pair data in compound design enabled the delivery of the highly potent, kinase-selective, and peripherally restricted clinical candidate PF-06273340.

Item Type:	Article
DOI/Identification number:	10.1021/acs.jmedchem.6b00850
Subjects:	Q Science > QD Chemistry > QD431 Organic Chemistry- Biochemistry- Proteins, peptides, amino acids R Medicine
Divisions:	Divisions > Division of Natural Sciences > Biosciences
Depositing User:	David Brown
Date Deposited:	02 Dec 2016 11:19 UTC
Last Modified:	05 Nov 2024 10:51 UTC
Resource URI:	https://kar.kent.ac.uk/id/eprint/59375 (The current URI for this page, for reference purposes)

University of Kent Author Information

Brown, David.

Creator's ORCID:	https://orcid.org/0000-0003-4605-4779
CReDIT Contributor Roles:

Depositors only (login required):

Altmetric

Total Views

Total unique views of this page since July 2020. For more details click on the image.